Drug-resistant infectious agents—those that are not efficiently killed or substantially growth-inhibited by antimicrobial compounds—are an increasingly important public health concern. Tuberculosis, gonorrhea, malaria and childhood ear infections are examples of diseases which have become more difficult to treat due to the emergence of drug-resistant pathogens. Antimicrobial resistance is becoming a factor in virtually all hospital-acquired (nosocomial) infections. It has been estimated that the annual cost of treating antibiotic resistant infections in the United States alone may be as high as $30 billion.
Antimicrobial resistance has been recognized since the introduction of penicillin nearly 50 years ago, when penicillin-resistant infections caused by Staphylococcus aureus rapidly appeared. Strains of Staphylococcus aureus resistant to methicillin and other antibiotics are endemic in hospitals. Infection with methicillin-resistant S. aureus (MRSA) strains may also be increasing in non-hospital settings. A limited number of drugs remain effective against these infections. However, S. aureus strains with reduced susceptibility to vancomycin have emerged recently in Japan and the United States. Strains of multidrug-resistant tuberculosis (MDR-TB) have emerged over the last decade and pose a particular threat to people infected with HIV. Drug-resistant strains are as contagious as those that are susceptible to drugs. Diarrheal diseases cause almost 3 million deaths a year—mostly in developing countries, where resistant strains of highly pathogenic bacteria such as Shigella dysenteriae, Campylobacter, Vibrio cholerae, Escherichia coli and Salmonella are emerging.
Given the escalating problems associated with poorly treatable infections caused by an increasing variety of resistant infectious agents, such as antibiotic-resistant bacteria, there is a great need for improved anti-microbial treatments. The two major avenues for research into such treatments are development of novel antimicrobial compounds and the development of agents which serve to reverse the resistance displayed by the pathogens. The current invention relates to compounds useful for reversing drug resistance and thus improving therapeutic treatment of infections associated with resistant pathogens.
Certain CNS drugs have beneficial effects on infections, either via inherent antibiotic properties, or via reversal of resistance to classical antibiotics. The use of members of the phenothiazine class of CNS drugs for reversal of multidrug resistance (MDR) is known in the art (Ramu et al. Cancer Chemother. Pharmacol. 1992, 30, 165). Among the phenothiazines, thioridazine has been reported to be effective in reversing resistance to a variety of antineoplastic agents in tumour cell lines (Akiyama et al. JNCI 1986, 76, 839). It has been suggested that the mechanism of action of thioridazine in such cell lines involves inhibition of drug efflux.
Furthermore, thioridazine has been suggested as a potential antituberculosis agent, based on its ability to kill Mycobacterium tuberculosis in vitro (Ordway et al. Antimicrobial Agents Chemother. 2003, 47, 917). Bactericidal and bacteriostatic properties of thioridazine have been recorded in a large number of bacterial strains (Radhakrishnan et al. Indian J. Exp. Biol. 1999, 37, 671).
The neuroleptic thioridazine (Melleril) is a racemic phenothiazine. The enantiomers of thioridazine have been resolved and well characterised (Patrick et al. Chirality 1991, 3, 208; GB 873,316; De Gaitani et al. Chirality 2003, 15, 479). Metabolism, providing several active metabolites, of thioridazine has been shown to be stereoselective (Eap et al. J. Chromatog. B: Biomed. Appl. 1995, 669, 271; Svendsen et al. Psychiatry Research 1988, 23, 1). The use of thioridazine racemate for reversal of resistance has been disclosed, and a potential mode of action discussed (Kristiansen, M., 5th European Congress on Chemotherapy and Infection, Rhodes, 2003).
The dextrorotatory (R) enantiomer of thioridazine has been ascribed more potent CNS-related activity than the racemate or levorotatory enantiomer. Recent studies have suggested that the levorotatory (S) form shows selectivity for D1-receptors, while the dextrorotatory isomer has high affinity for D2-receptors (Svendsen et al. Neuropharmacol. 1988, 27, 1117-25).
For the application of CNS-active drugs as antibacterials, such as those belonging to the phenothiazine class, it would clearly be beneficial to apply compounds with relatively low potency at e.g. dopamine receptors, but with potent antimicrobial activity, e.g. mediated via interactions with a bacterial efflux pump. Such compounds would be superior since side effects related to the neuropsychopharmacodynamic properties might be expected to be less pronounced. Thus, one advantage provided by the present invention is that lower doses of the CNS-active drugs phenothiazine antibacterials are required then presently used, leading to lesser side effects.
Thus, a benefit provided by the present invention is that a composition which comprises a the phenothiazine compounds of the invention and an anti-microbial agent, requires lower doses of the anti-microbial agent then presently used when attempting to treat infections. Thus, infections presently resistant and untreatable using a particular agent now become treatable using same agent. Furthermore, infections which required high doses of the anti-microbial agent now only need lower doses in the treatment of infections showing some resistance.